Authored by LI Nefyodov*
Introduction
There is comparatively little data in the available literature on changes in the spectrum (pool, fund) of free plasma amino acids against the background of atherosclerosis. Only a few works are devoted to a comparative assessment and interpretation of changes in the pool of free amino acids at different stages of atherosclerosis and in the dynamics of its treatment [19]. The question of the information content of the established changes in the levels of individual amino acids in atherosclerosis and their significance in comparison with other clinical and biochemical criteria remains practically unclear. The unresolved problem of the choice of individual amino acids in the amino acids used for the directed correction of metabolic imbalance in atherosclerosis.
The importance of amino acids in the regulation of the functions of pathological conditions (vasoaterogenesis, arterial thrombosis) of the cardiovascular system has been convincingly established in a number of studies. Repeatedly described is a decrease in blood lipid levels under the action of glycine and its derivatives, the positive effect of cysteine and aspartate in patients with hyperlipidemia, the lipid-lowering effect of arginine in plasma [12]. High concentrations of amino acids and their derivatives in platelets have been demonstrated [21], upon activation of which the agonist binds to a specific receptor, forming a complex through which an energy signal that activates phosphatase and mobilizes ionized calcium from the dense tubular system to the cytoplasm is transmitted [22]. A study of the amino acid sequences of glycoprotein receptor polypeptides that specifically bind hem coagulation substrates showed the possibility of inhibiting platelet aggregation, adhesion and blood clot formation using synthetic and natural (snake venom) polypeptides containing arginine, glycine, asparagine, valine, proline, phenylalanine and cysteine [23].
The role of free amino acids in the processes of tissue ischemia tolerance and post ischemic recovery deserves special attention [24]. The protective effect of branched chain amino acids - BCAA (valine, leucine, and isoleucine) in the myocardium is manifested in the maintenance of contractility, macroerg levels (ATP, creatinine phosphate), normalization of aortic and coronary blood flow, cardiac output and cardiac output. The BCAA activates the production of catabolites of the adenine system during post ischemic reperfusion, activates the utilization of introduced amino acids to high-energy substrates of Krebs cycle, and helps to restore the functional capabilities of smooth muscle structures [25].
Recently, the role of amino acid derivatives, biogenic amines, in the development of the pathology of the cardiovascular system, the progression of thrombosis and damage to the vascular wall with the simultaneous activation of platelet function has been proven [26]. An increase in the content of adrenaline and norepinephrine in the blood, together with an increase in the content of other vasoconstrictor biogenic amines in the blood of patients with atherosclerosis, has been established at an evidence-based level. The predominance of α-adrenergic receptors in arterial blood creates the conditions for the occurrence of vasoconstriction [27]. Thus, in patients with atherosclerosis, the activity of amino oxidase in the blood utilizing biogenic amines (serotonin, tyramine, and tryptamine) is significantly reduced, which creates the conditions for the manifestation of vascular effects of vasoconstrictor amines [28]. Platelet dense granules contain Ca2+, serotonin and other biogenic amines, ADP and ATP, secreted in the release reaction. Ca2+ ions are triggering factors in the formation of a platelet clot, spasm of blood vessels and acceleration of blood coagulation. Biogenic amines induce only primary aggregation [27]. The use of serotonin antagonists and the activation of catabolism enzymes of vasoconstrictor biogenic amines to eliminate the spastic component of ischemia seems to be a promising direction for the pathogenetic treatment of atherosclerosis. Thus, the functioning of the cardiovascular system is carried out according to the neuro-humoral regulatory mechanism, and the development of pathological conditions occurs with the involvement of various types of metabolism and cellular structures.
The adhesion-aggregation activity of platelets has a significant effect on the occurrence of thrombosis. As a result of platelet adhesion and aggregation, hemostasis is realized in small vessels. The emergence of adhesion is promoted by a change in the vascular wall, contact of platelets with collagen fibers, the release of ADP, biogenic amines, and traces of thrombin from damaged cells. Against the background of adhesion, platelet aggregation occurs, which is stimulated by ADP released from the formed elements of the blood as a result of the destabilization of their membranes under the action of prothrombinase. Platelet activation is a key step in the hemostatic process. Therefore, platelet activation is an essential stage of thermogenesis and vascular lesions [25,26].
The anti-atherogenic properties of the derivative of sulfurcontaining amino acids Tau may be due to the fact that the synthesis of taurocholates promotes lipid absorption, lipolysis, and absorption of fatty acids in the intestine. On the other hand, conjugation of taurine (Tau) with bile acids affects the elimination of cholesterol from the body and thereby controls cholesterogenesis [27]. When rats are kept on a high-fat diet supplemented with Tau, the latter inhibits the rise in cholesterol in the liver, inhibiting its intestinal absorption. In addition, at a dose of 250 and 500 mg / kg body weight, Tau activated the transport of cholesterol from the blood and its metabolism to bile acids [19]. Adding 300- 500 mg of Tau to the diet reduces the concentration of bile acids and cholesterol in monkey bile and enhances the synthesis of taurocholates in piglets [20]. It is possible that the high level of taurocholates in some species of mammals (rats) complicates the modeling of experimental atherosclerosis, because the rate of exchange of bile acids increases due to the formation of chlotaurin. The anti-atherogenic effect of S-adenosylmethionine, evaluated by increasing the level of glutathione and improving macro- and microcirculation, was investigated against the background of the atherogenic effect of cholesterol. S-adenosylmethionine is recommended as an additive in amino acid mixtures for parenteral nutrition. Currently, the best-known commercial preparations of S-adenosylmethionine in Europe are Samyr, Samet and Gambrel. Summarizing the above, it should be noted that the use of amino acid preparations for atherosclerosis is rational and the strategy for their use should be based on the elimination of the amino acid imbalance present in this disease, and the correction of the free sulfur-containing amino acids stock, including the use of taurine, whose anti-atherogenic properties should be considered quite promising [1-18].
Recently, new evidence has been obtained of the participation of amino acids in the pathogenesis of atherosclerosis. Thus, data were obtained on changes in extracellular levels of neurotransmitter amino acids during atherosclerotic brain damage - an increase in the concentration of both excitatory (glutamate, aspartate) and inhibitory amino acids (GABA and taurine) compared with the control [28]. It should be borne in mind that amino acids are not only important precursors for the synthesis of proteins and other N-containing compounds, but also participate in the regulation of the main metabolic pathways. For example, glutamate and aspartate are components of the malate/aspartate shunt, and their concentrations control the rate of mitochondrial oxidation of glycolytic NADH. Glutamate also controls the rate of urea synthesis not only as a precursor to ammonia and aspartate, but as a substrate for the synthesis of N-acetyl glutamate, a significant activator of carbonyl phosphate synthase. This mechanism allows the regulation of urea synthesis at a relatively constant concentration.
Certain amino acids (leucine) stimulate protein synthesis and inhibit autophagy degradation of the protein regardless of changes in cell volume, since they stimulate motor and protein kinase, which is one of the components of signal transduction of insulin. In the case of low energy supply of cells, motor stimulation with amino acids is inhibited by activation of camp-dependent protein kinase. Amino acid-dependent signaling also promotes insulin production by β-cells. This stimulates the anabolic effect of amino acids [29]. It is well known that the heart is “metabolically omnivorous” because it is able to actively oxidize fatty acids, glucose, ketone bodies, pyruvate, lactate, amino acids and even its structural proteins (in decreasing order of preference). The energy of these substrates provides not only mechanical contraction, but also the operation of various Tran’s membrane pumps and conveyors necessary to maintain ionic homeostasis, electrical activity, metabolism and myocardial catabolism. Cardiac ischemia and the resulting coronary and heart failure alter both the electrical and metabolic activity of the myocardium.
The preference for substrates has been little studied, although hypoxia during ischemia significantly changes the relative selectivity of the heart in the use of different substrates. Metabolic changes in heart rhythm disturbance are the main component of cardiac myopathies. At the same time, the potential contribution of amino acids to maintaining the electrical conductivity of the heart and stability during ischemia is underestimated. Despite the obvious evidence that amino acids have a cardio protective effect in ischemia and other cardiac disorders, their role in the metabolism of the ischemic heart has not yet been fully elucidated [30-32].
Studies on the determination of taurine and a number of amino acids predominant in the myocardium (glutamate, aspartate, glutamine and asparagine) in coronary insufficiency showed their differences in the content in the left and right ventricles in coronary insufficiency. A comparison of the levels of these amino acids in aortic stenosis and coronary heart disease in myocardial biopsy specimens showed higher concentrations of taurine in the left ventricle in both situations [33]. With severe, progressive cardio sclerosis in the rabbit myocardium, the content of phenylalanine and tyrosine increased, which was also found in patients with coronary heart disease, and the degree of increase in the level of amino acids changed depending on the clinical forms of coronary atherosclerosis (angina pectoris of various functional classes, myocardial infarction).
Methionine is a key essential amino acid, a donor of methyl groups and sulfur. It takes an active part in the metabolism of carbohydrates, fats and amino acids, the activation of antioxidant and detoxifying systems. Methionine serves as an essential precursor of cysteine, glutathione, taurine and, as a cysteine precursor, is involved in the synthesis of insulin and coenzyme A. Methylation processes (involving S – adenosylmethionine) are associated with gene expression, the functioning of the sympathoadrenal system, and the formation of choline and acetylcholine [33]. With regard to coronary heart disease, a special role is played by violations of the formation of methionine, leading to the accumulation in the blood and urine of its predecessor, homocysteine. Examination and treatment of patients with homocysteinuria revealed early and active development of atherosclerosis in young patients: hyperhomocysts (e) anemia is a significant risk factor for the development of atherosclerosis and coronary heart disease. Clinical studies have revealed a significant effect of methionine on the growth of smooth muscle cells, followed by vascular endothelial dysfunction and the development of arterial hypertension with a high risk of thrombosis. It has been established that elevated homocysteine levels can be reduced by adding folic acid and B vitamins to food products. High plasma homocysteine levels during myocardial ischemia accelerate the oxidation of low and very low-density lipoproteins, thereby enhancing the development of atherosclerosis, altering the coagulation cascade and increasing thrombogenicity of blood decreases. Homocysteine with the participation of homocysteine thiolactone has in vitro and in vivo direct damaging effects on endothelial cells, leading to impaired endothelial vasodilation factor. Elevated homocysteine levels enhance lipid peroxidation through the generation of hydrogen peroxide and superoxide radicals. In addition to these factors, an increase in homocysteine levels stimulates the growth of smooth muscle cells in the vascular wall, exacerbating the narrowing of the bloodstream.
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